This blog is a short version of the full length companion article which can be accessed here.

During the year and a half since the Food and Drug Administration Safety and Innovation Act (FDASIA) was signed into law, there has been much excitement and conversation about this new program.

In November 2013, Gazyva® (obinutuzumab, Roche/Genentech) and Imbruvica® (ibrutinib, Pharmacyclics/Johnson & Johnson) became the first FDA approved oncology agents with Breakthrough Therapy status. Gazyva was approved in combination with chlorambucil in patients with chronic lymphocytic leukemia (CLL); Imbruvica was approved as monotherapy in patients with mantle cell lymphoma (MCL). These approvals may provide the backdrop to ascertain whether and to what degree the Breakthrough Therapy designation can accelerate time to market.

Imbruvica experienced a fast time to market and a quick regulatory review, with the FDA approving the drug about three months before its PDUFA date. However, will agents with Breakthrough Therapy status consistently and repeatedly experience a speedy time to market or will Imbruvica’s fast time to market turn out to be a unique situation?

With a number of Breakthrough Therapies currently in the oncology pipeline, this question will hopefully be able to be addressed in the relatively near future. According to the FDA website, a total of 34 Breakthrough Therapy designations covering all indications, had been granted as of November 22, 2013 (note that this does not appear to represent the number of agents but rather the number of requests for the designation that have been granted).1

The applications and decisions for Breakthrough Therapies are currently confidential, and the sponsoring companies have not yet disclosed the identities of a minority of these granted Breakthrough designations. Of the 26 different Breakthrough Therapy agents that have been disclosed to date, one-half are in oncology indications.

Of the oncology agents currently in development that have been granted Breakthrough Therapy status, a number of them received the designation early in clinical development, some after the completion of Phase I trials (see Table 1). Considering the faster time to approval for Imbruvica compared with Gazyva, the pipeline agents that received Breakthrough Therapy status earlier in development are theoretically more likely to have a shorter length of clinical development and time to approval due to the greater opportunities to take advantage of the benefits of increased FDA interactions, advice and organizational commitment.

Indeed, there are already some indications that these agents will have compressed development timelines. After receiving Breakthrough Therapy status based on Phase I data, both LDK378 (Novartis) and lambrolizumab (MK-3475, Merck & Co.) initiated Phase III trials without waiting for Phase II data to become available. In addition, some of these agents will likely apply for accelerated approval based on Phase II data. For example, Novartis is guiding for a regulatory filing for LDK378 in 2014,2 and since the company’s two ongoing Phase III trials of LDK378 just started in the summer of 2013, this timing would have to represent a filing for accelerated approval. In Japan, Chugai recently submitted a marketing application for alectinib based on the results of a Phase I/II trial in Japanese patients, raising the possibility that Roche could follow the same strategy in the United States when the results of the company’s ongoing Phase II trial in U.S. patients become available.

It’s possible that some of these drugs would have sought accelerated approval based on early data even in the absence of Breakthrough Therapy status. Future development will be watched closely over the next few years to see if accelerated approval applications for agents with Breakthrough Therapy status occur with more frequency than has been historically observed, and also to see if the speedy time to market observed with Imbruvica can be repeated consistently for other Breakthrough Therapies.

Designing resource efficient development programs to identify drug candidates that should be advanced to late stage development and to determine the most useful trial design and/or target patient population for a Phase III trial are ongoing challenges for drug manufacturers. The I-SPY 2 trial is an innovative “find a winner” trial that aims to address some of these challenges by screening a number of different novel experimental agents in the neoadjuvant setting in combination with a standard chemotherapy regimen of paclitaxel followed by AC compared to standard chemotherapy alone. In this novel trial design, the randomization of patients to treatment arms is adaptive, with randomization probabilities continuing to be updated as the trial progressed. When an experimental treatment arm has enrolled 60-120 patients, an algorithm is used to decide whether that experimental regimen should “graduate.” Graduating from the trial is defined as having at least an 85% likelihood of success in a randomized Phase III trial in the neoadjuvant setting with a target enrollment of 300 patients and an endpoint of pathological complete response (pCR). Based on biomarker/subtype testing of patients after enrollment, experimental agents can graduate in a variety of patient segments, such as HER2+/HR-, triple negative disease, and HER2-/HR+.

Multiple pharmaceutical companies are participating in this trial, which to date has been investigating seven different experimental regimens. Results from the first experimental regimen to graduate, the combination of the PARP inhibitor veliparib (AbbVie) and carboplatin, were presented at 2013 San Antonio Breast Cancer Symposium (SABCS) annual meeting on Friday, December 13.1 Enrollment to the veliparib plus carboplatin experimental arm was only allowed for HER2- patients, making the regimen eligible to graduate in three different patient populations: all HER2- patients, HER2-/HR+ patients, and triple negative patients. A total of 72 patients were randomized to receive veliparib plus carboplatin in combination with standard neoadjuvant chemotherapy, and 44 HER2- patients who were concurrently randomized to receive standard neoadjuvant chemotherapy alone were used as a control.

The addition of veliparib and carboplatin to standard neoadjuvant chemotherapy improved the estimated pCR in triple negative patients, but not in HER2-/HR+ patients. Although actual pCR rates in the study arms were not calculated because of a concern over bias due to the adaptive randomization in the trial design, a Bayesian model was used to provide estimated pCR rates. In HER2-/HR+ patients, the estimated pCR rate was 14% in the veliparib/carboplatin arm and 19% in the control arm, with a 28% probability that the combination is superior to control. In this patient population, the veliparib/carboplatin arm met the criteria for futility, with a 9% predictive probability of success in a Phase III trial. In contrast, the estimated pCR rate in triple negative patients was 52% in the veliparib/carboplatin arm compared to 26% in the control arm, with a 99% probability that the combination is superior to the control. In this patient population, the veliparib/carboplatin arm met the trial’s criteria for graduation, with a 90% predictive probability of success in a Phase III trial.

While the utility of the I-SPY 2 trial design will not be able to be fully evaluated until after the drug regimens in multiple experimental arms either meet criteria for futility or graduate and are subsequently advanced through successful Phase III programs, these data provide an early signal of the benefits of this novel trial design. With the efficient, collaborative design of this trial, data were able to be provided on the efficacy and potential Phase III success of the veliparib/carboplatin regimen in multiple patient segments based on enrollment of fewer than 100 patients into the experimental arm. Of course, these data are not without caveats; for example, the trial design does not allow for a comparison that could evaluate the relative contributions of the veliparib portion of the regimen and the carboplatin portion of the regimen to the efficacy of the combination. Theoretically, it could be possible that the enhanced efficacy of the regimen is due primarily to the effect of the added carboplatin, and results from an additional trial would be necessary to determine whether or not that is the case. However, for an agent like veliparib, which, if it does enter Phase III development, would be competing with other PARP inhibitors like BMN 673 (BioMarin) and olaparib (AstraZeneca) in a race to be the first agent in this drug class to enter the market for breast cancer, the benefits of this type of collaborative, relatively high throughput type of screening in early stage clinical development will likely provide an important benefit of identifying an appropriate patient population for late stage development, with potentially less time and cost. The results of additional I-SPY 2 experimental arms, as well as the results of late stage development of I-SPY 2 graduates (Puma Biotechnology recently announced the graduation of neratinib in HER2+/HR- patients; Puma press release, December 4, 2013), will be eagerly awaited to see if the potential benefits of this type of innovative trial will be borne out in practice.

There are a variety of known risk factors for developing breast cancer, such as obesity, nulliparity, and age at time of menarche and menopause.1 For patients with a particularly high risk of developing breast cancer, including those who have a family history of the disease or have tested positive for deleterious BRCA1 or BRCA2 mutations, there are several options available for risk reduction. Patients may receive closer breast cancer screening, prophylactic mastectomy or oophorectomy, or treatment with a chemoprevention agent. Currently, two hormonal agents, tamoxifen and raloxifene, are FDA approved to reduce the risk of breast cancer in patients at high risk of developing the disease. Exemestane, an aromatase inhibitor (AI), is another agent available for chemoprevention; although it has not been approved by the FDA for this purpose, it has a Category 1 recommendation in the National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines.2

At a session on December 12 at the San Antonio Breast Cancer Symposium (SABCS) 2013 annual meeting, results were presented from the Phase III IBIS-II trial that evaluated whether another AI, anastrozole, can prevent the development of breast cancer in women at increased risk of the disease.3 This trial randomized 3,684 post-menopausal women aged 40-70 at increased risk of developing breast cancer to receive either placebo or anastrozole (1 mg/day) for a period of five years. Patients could be classified as high risk based on a variety of factors, such as family history, atypia/LCIS, or increased breast density.

After seven years of follow-up time, there was a significantly lower incidence of all breast cancer (2.8% vs. 5.6%, HR=0.47, p<0.0001) and estrogen receptor (ER)-positive invasive breast cancer (1.4% vs. 3.3%, HR=0.42, p<0.001) in the anastrozole arm compared to the placebo arm (see Table 1). A subgroup analysis found that this benefit of anastrozole treatment applied to the development of DCIS (HR=0.47) and invasive ER-positive invasive breast cancer (HR=0.42), but there didn’t appear to be a benefit in preventing the development of invasive ER- breast cancer (HR=0.78, confidence interval crossed “1”).

In the chemoprevention setting where a drug is administered to patients who are currently healthy, safety takes on increased importance. Importantly, anastrozole was well-tolerated by patients. There was an increase in musculosketal adverse events (primarily arthralgia, joint stiffness, and carpal tunnel) in the anastrozole arm (63.9% vs. 57.8%), but since there was such a high rate of musculosketal AEs in the placebo arm, most of these AEs are probably not treatment related. There was also a slight and non-significant increase in the incidence of fractures in patients who received anastrozole (8.5% vs. 7.7%), an important consideration since treatment of breast cancer patients with an AI generally results in decreased bone mineral density. Interestingly, Dr. Cuzick, who presented the data, also mentioned that there was a reduction in other (non-breast) cancers in the anastrozole arm, mainly skin cancers, but because that slide was missing from the presentation, the audience was unable to evaluate those data. As would be expected with five years of drug therapy in healthy people, compliance decreased in both arms across the five years of treatment; at the end of treatment, the compliance rate was slightly but significantly lower in the anastrozole arm (68% vs. 72%, HR=0.84, p<0.005).

How do these data from the IBIS-II trial compare to the data for other chemoprevention agents in breast cancer? In the Phase III NSABP P1 trial, the risk ratio of the development of invasive breast cancer with tamoxifen compared to placebo was 0.51 after 69 months of follow-up time.4 During an 81 month (almost 8 years) follow-up of STAR trial comparing raloxifene to tamoxifen in high risk patients, raloxifen was less effective than tamoxifen in reducing the incidence of invasive breast cancer in high risk patients (risk ratio = 1.24).5 Although tamoxifen appears to be more effective than raloxifene, it comes along with a number of toxicities, including increased incidence of invasive endometrial cancers. In the MAP.3 trial, exemestane reduced the incidence of invasive breast cancer compared to placebo with an impressive hazard ratio of 0.33, with a more benign safety profile than tamoxifen.6 From the IBIS-II results, it appears that anastrozole is more effective and less toxic than tamoxifen; compared to exemestane, it appears to be slightly less effective, with a relatively similar safety profile.

Although longer-term follow-up data for anastrozole will likely be necessary to confirm a reasonable safety profile in this setting, the IBIS-II data suggest that anastrozole could be a new option for breast cancer chemoprevention. However, will it be utilized in practice? Although tamoxifen was approved by the FDA 15 years ago to reduce the development of breast cancer in high risk patients, it is rarely utilized in high-risk patients.7,8 This lack of utilization is likely due to the safety profile of tamoxifen; it could be daunting for a generally healthy high-risk patient to consider the prospect of multiple years of a treatment that can be accompanied by non-trivial adverse events. In this setting, a benign safety profile of a drug will likely be critical for utilization.

In addition, competitive landscape in this segment of the market is complicated by the fact that the different available agents for breast cancer chemoprevention are not only competing against each other, but they are competing against other non-drug treatment options, such as prophylactic mastectomy. While this type of prophylactic surgery can certainly have its own downsides, it does have the advantage of taking a shorter amount of time compared to the long five year commitment for treatment with hormone therapies. It is also probable that patient preferences for the different treatment options available for breast cancer prevention in high risk patients could be influenced by media coverage and popular trends, such as the flood of media coverage of prophylactic mastectomy when actress Angelina Jolie elected to undergo this type of surgery after testing positive for a BRCA mutation. However, for this type of very personal decision, an increasing number of available options can only be a positive development for patients.